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Activation of p38 mitogen-activated protein kinase is required for death receptor-independent caspase-8 activation and cell death in response to sphingosine.
Mol Cancer Res. 2009 Mar; 7(3):361-70.MC

Abstract

Sphingosine induces activation of multiple signaling pathways that play critical roles in controlling cell death. However, the precise molecular mechanism of cell death induced by sphingosine remains to be clarified. In this study, we show that sphingosine induces death receptor-independent caspase-8 activation and apoptotic cell death via p38 mitogen-activated protein kinase (MAPK) activation and that suppression of the MAPK/extracellular signal-regulated kinase (ERK) kinase/ERK pathway by protein phosphatase 2A (PP2A) is required for p38 MAPK activation. Treatment of cells with sphingosine induced suppression of ERK and activation of p38 MAPK. Inhibition of p38 MAPK led to the marked suppression of death receptor-independent caspase-8 activation and subsequent cell death induced by sphingosine. Interestingly, pretreatment with phorbol 12-myristate 13-acetate or transfection of MAPK/ERK kinase/ERK resulting in ERK activation completely attenuated sphingosine-induced p38 MAPK activation. PP2A activity was additionally elevated on sphingosine treatment. Small interfering RNA targeting of PP2A effectively attenuated sphingosine-induced p38 MAPK activation through restoration of ERK activity, suggesting PP2A-mediated opposing regulation of ERK and p38 MAPK. Our findings clearly imply that activation of p38 MAPK promotes death receptor-independent activation of caspase-8 and apoptotic cell death pathways, thus providing a novel cellular mechanism for the anticancer activity of sphingolipid metabolites.

Authors+Show Affiliations

Department of Chemistry, Hanyang University, Seoul, Korea.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

19276187

Citation

Yoon, Chang-Hwan, et al. "Activation of P38 Mitogen-activated Protein Kinase Is Required for Death Receptor-independent Caspase-8 Activation and Cell Death in Response to Sphingosine." Molecular Cancer Research : MCR, vol. 7, no. 3, 2009, pp. 361-70.
Yoon CH, Kim MJ, Park MT, et al. Activation of p38 mitogen-activated protein kinase is required for death receptor-independent caspase-8 activation and cell death in response to sphingosine. Mol Cancer Res. 2009;7(3):361-70.
Yoon, C. H., Kim, M. J., Park, M. T., Byun, J. Y., Choi, Y. H., Yoo, H. S., Lee, Y. M., Hyun, J. W., & Lee, S. J. (2009). Activation of p38 mitogen-activated protein kinase is required for death receptor-independent caspase-8 activation and cell death in response to sphingosine. Molecular Cancer Research : MCR, 7(3), 361-70. https://doi.org/10.1158/1541-7786.MCR-08-0069
Yoon CH, et al. Activation of P38 Mitogen-activated Protein Kinase Is Required for Death Receptor-independent Caspase-8 Activation and Cell Death in Response to Sphingosine. Mol Cancer Res. 2009;7(3):361-70. PubMed PMID: 19276187.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Activation of p38 mitogen-activated protein kinase is required for death receptor-independent caspase-8 activation and cell death in response to sphingosine. AU - Yoon,Chang-Hwan, AU - Kim,Min-Jung, AU - Park,Moon-Taek, AU - Byun,Joo-Yun, AU - Choi,Young-Hyun, AU - Yoo,Hwan-Soo, AU - Lee,Yong-Moon, AU - Hyun,Jin-Won, AU - Lee,Su-Jae, Y1 - 2009/03/10/ PY - 2009/3/12/entrez PY - 2009/3/12/pubmed PY - 2009/5/1/medline SP - 361 EP - 70 JF - Molecular cancer research : MCR JO - Mol Cancer Res VL - 7 IS - 3 N2 - Sphingosine induces activation of multiple signaling pathways that play critical roles in controlling cell death. However, the precise molecular mechanism of cell death induced by sphingosine remains to be clarified. In this study, we show that sphingosine induces death receptor-independent caspase-8 activation and apoptotic cell death via p38 mitogen-activated protein kinase (MAPK) activation and that suppression of the MAPK/extracellular signal-regulated kinase (ERK) kinase/ERK pathway by protein phosphatase 2A (PP2A) is required for p38 MAPK activation. Treatment of cells with sphingosine induced suppression of ERK and activation of p38 MAPK. Inhibition of p38 MAPK led to the marked suppression of death receptor-independent caspase-8 activation and subsequent cell death induced by sphingosine. Interestingly, pretreatment with phorbol 12-myristate 13-acetate or transfection of MAPK/ERK kinase/ERK resulting in ERK activation completely attenuated sphingosine-induced p38 MAPK activation. PP2A activity was additionally elevated on sphingosine treatment. Small interfering RNA targeting of PP2A effectively attenuated sphingosine-induced p38 MAPK activation through restoration of ERK activity, suggesting PP2A-mediated opposing regulation of ERK and p38 MAPK. Our findings clearly imply that activation of p38 MAPK promotes death receptor-independent activation of caspase-8 and apoptotic cell death pathways, thus providing a novel cellular mechanism for the anticancer activity of sphingolipid metabolites. SN - 1541-7786 UR - https://www.unboundmedicine.com/medline/citation/19276187/Activation_of_p38_mitogen_activated_protein_kinase_is_required_for_death_receptor_independent_caspase_8_activation_and_cell_death_in_response_to_sphingosine_ L2 - http://mcr.aacrjournals.org/cgi/pmidlookup?view=long&pmid=19276187 DB - PRIME DP - Unbound Medicine ER -